DESCRIPTION: (Applicant's Abstract) Opiate tolerance and dependence are complex phenomena, and may involve, in part, alterations in endogenous opioid peptide concentrations. We will examine the effects of chronic mu opiate receptor agonists on concentrations of endogenous opioid peptides and mu opiate receptors. Specific Aim I will address the effects of chronic of morphine, endomorphin-1 and 2 (two newly discovered endogenous mu agonists) on the levels of mu receptors, endomorphin-1 and 2 in SH-SYSY cells, using radioimmunoassay (with antibodies generated and characterized in this lab). Specific Aim II will address the effects of chronic morphine, and endomorphin-1 and -2 administration on the levels of mu receptors and endomorphin- l and 2 in the rat spinal cord, using immunocytochemistry. In order to examine the mu opiate receptor's role in regulating endomorphin-1 and 2 peptide levels, in Specific Aim III, we will inactivate the mu opiate receptor in the rat spinal cord, and analyze the changes in endomorphin- I and 2 levels, using immunocytochemistry. Elucidation of the effects of chronic opiate administration on endogenous opioid peptide systems will help us to develop an understanding of the mechanisms of opiate tolerance and dependence.